The long-term goal of our research is to understand the mechanisms regulating growth and differentiation of mandibular condylar cartilage. The mandibular condylar cartilage is derived from periosteum and comprised of 4 zones that contain cells at various stages of endochondral ossification. The mandibular condylar cartilage remodels in response to external mechanical strains by regulating chondrogenesis and endochondral ossification, in order to achieve a better balance between mechanical stress and the load bearing capacity of the joint. Estrogen regulates mandibular condylar cartilage growth and differentiation. It is known that the estrogen-mediated inhibition of mechanical loading-induced periosteal bone formation and axial skeletal growth requires estrogen receptor beta (ER). However, the mechanisms underlying the regulatory effects of estrogen in the mandibular condylar cartilage remain unknown. The general objective of this application is to examine the effects of estrogen status on the regulation of mandibular condylar cartilage growth induced by mechanical loading. Our central hypothesis is that estrogen acts through ER to inhibit chondrocyte maturation in the mandibular condylar cartilage in female mice and will, therefore, affect the response of condylar cartilage to mechanical stress. To test this hypothesis, the following Specific Aims will be examined; Specific Aim 1: Examine mandibular condylar growth in ER deficient mice. Basal Mandibular condylar cartilage growth and differentiation in male and female wild type (WT) and ER2 deficient mice will be assessed. In addition, mandibular condylar growth will be examined in sham or ovariectomized WT and ER deficient mice treated with or without estrogen. Specific Aim 2: Examine the role of ER in the regulation of mandibular condylar cartilage differentiation in TMJ loading models. Two in vivo TMJ mechanical loading models, which cause either an increase or a decrease in mandibular chondrocyte differentiation, will be applied to male and female WT and ER deficient mice. Mandibular condylar growth and differentiation will be assessed from both models. Greater understanding on how mandibular condylar cartilage remodeling is controlled by estrogen and mechanical loading will aid in the understanding of diseases of the temporomandiblar joint (TMD), which have a predilection for women between the ages of 18 and 45, and may also lead to new approaches to joint regeneration.